Oxidized redox state, a new potential biomarker for prostate cancer progression

氧化还原态，前列腺癌进展的新潜在生物标志物

基本信息

批准号：
9039015
负责人：
Luksana Chaiswing
金额：
$ 20.62万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039015
关键词：
4 hydroxynonenal Acceleration Advanced Malignant Neoplasm Affect Antibodies Antioxidants Benign Biochemical Biological Biological Markers Cancer Etiology Cations Cells Cessation of life Characteristics Clinical Couples Cysteine Cystine DNA Sequence Alteration Deoxyguanosine Detection Development Diagnosis Disease Disseminated Malignant Neoplasm Environment Epigenetic Process Epithelial Epithelium Equilibrium Exhibits Freezing Future Gleason Grade for Prostate Cancer Glutathione Glutathione Disulfide Health High Pressure Liquid Chromatography Human Image Image Analysis Imaging technology Immunohistochemistry LNCaP Lead Life Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Methods Molecular Monitor Mus Mutation Neoplasm Metastasis Nuclear Nude Mice Oxidants Oxidation-Reduction Oxidative Stress PC3 cell line Pathologic Pathologic Processes Pathological Staging Patients Post-Translational Protein Processing Production Property Prostate Proteins Public Health Reactive Nitrogen Species Reactive Oxygen Species Resolution Role Sampling Scanning Sensitivity and Specificity Signal Transduction Site Staging Staining method Stains Sulfhydryl Compounds System TXN gene Techniques Time Tissue Microarray Tissues Transplantation Tumor Suppressor Genes Variant Western Blotting Xenograft procedure base cancer diagnosis clinically relevant comparative extracellular imaging modality improved in vivo interest liquid crystal polymer male men mortality outcome forecast overexpression oxidation oxidative DNA damage oxidative damage potential biomarker prognostic protein expression response sensor specific biomarkers standard of care targeted treatment tempol therapeutic target tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is an increasingly common malignancy worldwide; progression to advanced cancer is highly unpredictable, resulting in a need for new clinically relevant biomarkers or diagnosis tools. A better understanding of PCa pathologic progression would allow development of more sensitive and specific biomarkers. Based on preliminary results from analyses of human PCa tissues, oxidized redox state and posttranslational modification of thioredoxin 1 (Trx1) protein levels were significantly increased in primary PCa with high Gleason scores and metastatic PCa in comparison to adjacent benign tissues. We hypothesize that increased oxidized redox state is contributed to redox imbalance in PCa, leading to increased production of reactive oxygen species/reactive nitrogen species, oxidative DNA damage, mutation of tumor suppressor genes, epigenetic changes, and subsequent PCa progression. To fully understand the relationship of oxidized redox state and PCa progression, a first step involves determining the correlation of oxidized redox state with PCa progression in patient samples. In Specific Aim 1, human PCa-tumor microarrays with different pathological stages will be constructed, stained with oxidative damage products and analyzed using Vectra/Nuance system. Additionally, thiol redox couples will be measured in human prostate frozen tissues with different pathological stages compared to adjacent benign epithelial prostate tissues. Defining the redox state of PCa and its correlation with disease stage is a necessary first step to determine 1) if oxidized redox state may potentially be used as biomarker for PCa diagnosis and 2) whether oxidized redox state is the cause or consequence of PCa progression. Biochemical analyses of redox state in Aim 1 are time-and labor-intensive and require a large amount of tissues. To overcome these problems, Specific Aim 2 will evaluate if TEMPOL-enhanced MRI could potentially be used in the diagnosis of intracellular redox state of prostate cancer in vivo. TEMPOL can undergo oxidation to the corresponding oxoammonium cation by variant oxidants and its paramagnetism property can be captured by MRI. Oxidizing tissues will exhibit longer-lived MRI signal than reducing tissues. We will scan nude mice with orthotopic xenograft transplant LNCaP-luc-M6 or PC3M-luc-C6 cells to evaluate the possibility and validity of TEMPOL-enhanced MRI. To our knowledge, the present proposal will be the first to 1) attempting correlate tissue redox status with the aggressiveness of PCa in patient samples and 2) use cutting edge technique, TEMPOL enhanced MRI to visualize redox state and diagnosis of PCa. Upon completion of these studies, a better understanding of PCa pathologic/metabolic progression may allow development of more sensitive, more relevant, and more specific biomarkers for early prediction or prognosis of those patients destined for clinical cancer progression.

描述（由适用提供）：前列腺癌（PCA）是全球越来越普遍的恶性肿瘤；向晚期癌症的发展是高度可预测的，导致需要新的临床相关生物标志物或诊断工具。对PCA病理发展的更好理解将允许发展更敏感和特定的生物标志物。基于对人PCA组织的分析的初步结果，氧化的氧化还原状态和硫氧还蛋白1（TRX1）蛋白水平的翻译后修饰在高振荡和转移性PCA的原代PCA中显着增加，与邻近的良性组织相比。我们假设增加的氧化氧化还原态有助于PCA的氧化还原失衡，从而导致活性氧/反应性氮种的产生增加，氧化性DNA损伤，肿瘤抑制基因的突变，表观遗传变化以及随后的PCA进展。为了充分了解氧化的氧化还原状态和PCA进展的关系，第一步涉及确定氧化氧化还原态与患者样品中PCA进展的相关性。在特定的目标1中，将构建具有不同患者学阶段的人类PCA肿瘤微阵列，用氧化损伤产物进行染色，并使用Vectra/Nuance系统进行分析。另外，与相邻的良性上皮前列腺组织相比，将在人类前列腺冷冻组织中测量硫醇氧化还原夫妇。定义PCA的氧化还原状态及其与疾病阶段的相关性确定1）确定氧化的氧化还原状态是否可能被用作PCA诊断的生物标志物； 2）氧化氧化还原状态是否是PCA进展的原因或后果。 AIM 1中氧化还原状态的生化分析是时间和劳动力密集的，需要大量组织。为了克服这些问题，特定的目标2将评估是否可以在体内前列腺癌的细胞内氧化还原状态诊断中使用tempol增强的MRI。 Tempol可以通过变异氧化剂对相应的oxoammonium阳离子进行氧化，而其磁磁性特性可以通过MRI捕获。与减少组织相比，氧化组织将执行更长的MRI信号。我们将用原位异种移植移植LNCAP-LUC-M6或PC3M-LUC-C6细胞扫描裸鼠，以评估tempol增强MRI的可能性和有效性。据我们所知，本提案将是第一个到1）尝试将组织氧化还原状态与PCA在患者样品中的侵略性相关联和2）使用尖端技术，Tempol增强了MRI来可视化PCA的氧化还原状态和诊断。完成这些研究后，对PCA病理/代谢进展的更好了解可能会使更敏感，更相关，更具体的生物标志物用于早期预测或进展，以预测到那些注定临床癌症进展的患者。